Declining immune function is well described in the elderly, and contributes significantly to increased risk and severity of infection, impaired responses to vaccination, and poorer control of cancer. Infections with several pathogens, whether viral (e.g., herpes viruses), bacterial (e.g., Mycobacteria) or parasitic (e.g., Leishmania), persist for the lifetime of the host. Reactivation of such persistent infections is a common consequence of waning immune function in the elderly. Regulatory T cells (Treg), a specialized subset of CD4+ T cells that have recently been shown to control the intensity of immune responses accumulate dramatically with age. While Treg negatively regulate immune responses, it is currently unclear whether their accumulation contributes negatively to immune function in the elderly. Our preliminary data in elderly humans and in a mouse model of Leishmania major infection show that Treg actively suppress the functionality oe found that aged Treg express increased levels of IL-7R1 and decreased levels of the pro-apoptotic molecule, Bim, and that expression of both of IL-7R1 and Bim are modulated by IL-2. Although IL-2 and IL-7 signaling can antagonize Bim-driven apoptosis, the underlying mechanisms remain unclear. Our data suggest that IL-7 drives cytosolic retention of FOXO3a, a major Bim transcriptional regulator, which may control Bim expression in aged Treg. Together, our data suggest a model in which chronic IL-2 signaling increases in vivo survival of Treg by enhancing IL-7-driven signals that lead to FOXO3a-dependent suppression of Bim expression. Two inter-related hypotheses: (i) age-dependent accumulation of Treg occurs through increased peripheral survival of Treg;(ii) Treg accumulation contributes directly to immune suppression in aging hosts, will be tested in experiments outlined in three Specific Aims. One, we will define the mechanisms of increased accumulation of Treg in aged animals. T is well described in the elderly, and contributes significatly to increased risk and severity of infection, impaired responses to vaccination, and poorer control of cancer. Mechanisms underlying declining immune function in the elderly remain unclear, but are critical to our ability to design innovative therapies. We have found that a "suppressive" population of T cells accumulates in aging mice and humans. The proposal explores the mechanisms responsible for the accumulation of these suppressive cells and whether or not they can be manipulated to improve immune function in the aging.